Overview of Kidney Development

The permanent mammalian kidney is derived from the metanephros. Establishment of the metanephric kidney is preceded by formation of two other mesenchyme-derived kidney-like structures—the pronephros and the mesonephros. Both are transient kidney-like paired structures that do not contribute to the permanent kidney. The pronephros is the more anterior of these structures and degenerates in mammals. The more posterior structure, the mesonephros, gives rise to male reproductive organs including the rete testis, efferent ducts, epididymis, vas deferens, seminal vesicle, and prostate. In females, the mesonephric portion of the wolffian duct degenerates.

The metanephric kidney is composed of the metanephric mesenchyme and the ureteric bud, both of which are derived from the intermediate mesoderm ( Fig. 2.1 ). Metanephric mesenchyme is the tissue source of all epithelial cell types comprising the mature nephron. The ureteric bud originates as an epithelial outgrowth of the caudal portion of the wolffian duct (also termed the mesonephric or nephric duct ) (see Fig. 2.1A ). Reciprocal inductive interactions between the metanephric mesenchyme and the ureteric bud result in (1) nephrogenesis, defined as formation of the glomerulus and all tubules proximal to the collecting ducts, and (2) branching morphogenesis, defined as growth and branching of the ureteric bud and subsequent formation of the renal collecting system, which is constituted by the cortical and medullary collecting ducts, the renal calyces, and the renal pelvis.

Stages of kidney formation.

(A) Induction of the metanephric mesenchyme by the ureteric bud promotes aggregation of mesenchyme cells around the tip of the ureteric bud. (B) Polarized renal vesicles are formed. (C) Stromal cells secrete factors that influence nephrogenesis and branching morphogenesis. (D) Formation of the S -shaped body involves the formation of a proximal cleft that is invaded by angioblasts. (E) The complete nephron is joined to the collecting duct. (F) Glomerulus demonstrating organization of the capillary tuft, podocytes, and parietal epithelial cells.

Development of the Renal Collecting System

The ureteric bud arises from the wolffian duct in response to signals elaborated by the adjacent metanephric mesenchyme at week 5 of human fetal gestation. Failure to induce ureteric bud outgrowth results in renal agenesis, while outgrowth of more than one ureteric bud can result in kidney malformations including a double collecting system and duplication of the ureter. The position at which the ureteric bud arises from the wolffian duct relative to the metanephric mesenchyme is critical to the nature of the interactions between the ureteric bud and the metanephric mesenchyme. Ectopic positioning of the ureteric bud is associated with renal tissue malformation (dysplasia), which may result from abnormal ureteric bud-metanephric mesenchyme interactions. Ectopic positioning of the ureteric bud is also thought to contribute to the integrity of the ureterovesical junction.

Branching of the ureteric bud occurs immediately following invasion of the metanephric mesenchyme by the ureteric bud. The number of ureteric bud branches is a major determinant of final nephron number, since ureteric bud branch tips induce discrete subsets of metanephric mesenchyme cells to undergo nephrogenesis. Repetitive branching events (see Fig. 2.1C ) result in the formation of approximately 15 branch generations. In humans, the first nine branch generations are formed by approximately 15 weeks’ gestation. Concomitant with formation of these branches, new nephrons are induced by reciprocal inductive interactions between newly formed ureteric branch tips and surrounding metanephric mesenchyme. By the 20th to 22nd week of gestation, ureteric branching is completed. Thereafter, collecting duct development occurs by extension of peripheral branch segments, and new nephrons form predominantly around the tips of terminal collecting duct branches.

Between the 22nd and 34th week of gestation, the peripheral (cortical) and central (medullary) domains of the developing kidney are established. The renal cortex, which represents 70% of total kidney volume at birth, becomes organized as a relatively compact, circumferential rim of tissue surrounding the periphery of the kidney. The renal medulla, which represents 30% of total kidney volume at birth, has a modified cone shape with a broad base contiguous with cortical tissue. The apex of the cone is formed by convergence of collecting ducts in the inner medulla and is termed the papilla. Distinct morphologic differences emerge between collecting ducts located in the medulla and those located in the renal cortex. Medullary collecting ducts are organized into elongated, relatively unbranched linear arrays, which converge centrally in a region devoid of glomeruli. In contrast, collecting ducts located in the renal cortex continue to induce metanephric mesenchyme. The most central segments of the collecting duct system, formed from the first five generations of ureteric bud branching, undergo remodeling by increased growth and dilatation of these tubules to form the pelvis and calyces.

Formation of the Nephron

Nephrons arise from metanephric mesenchyme cells via a process termed nephrogenesis . Cells adjacent to the invading ureteric bud are induced to undergo a mesenchymal to epithelial transformation. Initially, mesenchyme cells aggregate to form a four- to five-cell-thick layer, termed a cap condensate , around the ampulla of the advancing ureteric bud (see Fig. 2.1A ). Near the interface of the ampulla and its adjacent ureteric branch, a cluster of cells separates from the cap condensate and forms an oval mass, called a pretubular aggregate (see Fig. 2.1B ). An internal cavity forms within the pretubular aggregate, at which point the structure is called a renal vesicle. Multipotential precursors residing in renal vesicles give rise to all the epithelial cell types of the nephron. Nephron segmentation into glomerular and tubular domains is initiated by the sequential formation of two clefts in the renal vesicle. Creation of a lower cleft, termed the vascular cleft , precedes formation of the comma-shaped body. Generation of an upper cleft in the comma-shaped body precedes formation of an S -shaped body, which is characterized by three segments or limbs (see Fig. 2.1D ). The middle limb gives rise to the proximal convoluted tubule and the upper limb to the descending and ascending limbs of the loops of Henle and the distal convoluted tubule.

Formation of the glomerulus begins as the vascular cleft broadens and deepens and as the lower limb of the S -shaped body forms a cup-shaped unit (see Fig. 2.1D and F ). Epithelial cells lining the inner wall of this cup will comprise the visceral glomerular epithelium, or podocyte layer. Cells lining the outer wall of the cup will form the parietal glomerular epithelium that line the Bowman capsule (see Fig. 2.1F ). The glomerular capillary tuft is formed via recruitment and proliferation of endothelial and mesangial cell precursors. Recruitment of angioblasts and mesangial precursors into the vascular cleft results in deformation of the lower S -shaped body limb into a cup-like structure (see Fig. 2.1E ). A primitive vascular plexus forms at this capillary loop stage. Podocytes of capillary loop stage glomeruli lose mitotic capacity and begin to form actin-based cytoplasmic extensions, or foot processes, and specialized intercellular junctions, termed slit diaphragms. Subsequent development of the glomerular capillary tuft involves extensive branching of capillaries and formation of endothelial fenestrae. Mesangial cells, in turn, populate the core of the tuft and provide structural support to capillary loops through the deposition of extracellular matrix. The full complement of glomeruli in the fetal human kidney is attained by 32 to 34 weeks when nephrogenesis ceases. Subsequent glomerular development involves hypertrophy, and glomeruli reach adult size by years of age.

Definition and Overview

Renal-urinary tract malformations are classified under the overall term, C ongenital A nomalies of the K idney and U rinary T ract (CAKUT). These malformations are the most frequently detected abnormalities during intrauterine life (0.1 to 0.7 pregnancies) and are the major cause of childhood kidney failure. In 30% of affected patients, CAKUT occurs in combination with nonrenal malformations as part of a genetic syndrome. Over 200 distinct syndromes feature some type of kidney and urinary tract malformation ( Table 2.1 ).

A classification of kidney and urinary tract malformations follows:

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  Aplasia (agenesis): congenital absence of kidney tissue

  
  
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  Simple hypoplasia: kidney length more than 2 standard deviations below the mean for age, with a reduced nephron number but normal kidney architecture

  
  
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  Dysplasia ± cysts: malformation of tissue elements

  
  
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  Isolated dilatation of the renal pelvis ± ureters (collecting system)

  
  
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  Anomalies of position including the ectopic and fused (horseshoe) kidney

Kidney and urinary tract malformations may be unilateral or bilateral, and, in 50% of affected patients, anomalies of the kidney are associated with structural abnormalities of the lower urinary tract. These structural abnormalities include vesicoureteral reflux (VUR) (25% of cases), ureteropelvic junction obstruction (11% of cases), and ureterovesical junction obstruction (11% of cases). Renal dysplasia is a polymorphic disorder characterized at the microscopic level by abnormal differentiation of mesenchymal and epithelial elements, decreased nephron number, loss of the demarcating zone between the cortex and the medulla, and metaplastic transformation of mesenchyme to cartilage and bone. Dysplastic kidneys range in size from large distended kidneys with multiple large cysts to small kidneys, with or without cysts. A small dysplastic kidney without macroscopic cysts, imaged by ultrasound, is classified as hypoplastic/dysplastic in the absence of a pathologic examination, which distinguishes between simple hypoplasia and dysplasia. The multicystic dysplastic kidney (MCDK) is an extreme form of renal dysplasia.

Etiology of Human Renal-Urinary Tract Malformation

CAKUT most often occurs in a sporadic manner such that neither a syndrome nor a mendelian pattern of inheritance is obvious. In probands with bilateral renal agenesis or bilateral renal dysgenesis and without evidence of a genetic syndrome or a family history, 9% of first-degree relatives have some type of malformation in the kidney and/or lower urinary tract apparent on ultrasound. An underlying genetic cause may be identified in both sporadic and inherited forms of CAKUT ( Table 2.2 ). In approximately 30% of CAKUT, kidney and/or urinary tract malformation occurs as part of a genetic syndrome, a chromosomal disorder, or an inborn error of metabolism with additional nonkidney manifestations (see Table 2.1 ).

Table 2.2

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